Congenital Diaphragmatic Hernia New Concept in Management STEPHEN J. SHOCHAT, M.D., RICHARD L. NAEYE, M.D., W. D. A. FORD, M.B., F.R.C.S., VICTOR WHITMAN, M.D., M. JEFFREY MAISELS, M.D.

The newborn infant with a congenital diaphragmatic hernia (CDH) who develops severe respiratory distress requiring operative repair within the first 24 hours of life represents one of the most challenging problems in pediatric surgery. The mortality in these infants still exceeds 50% and has historically been attributed to ventilatory insufficiency secondary to pulmonary hypoplasia. However, the primary abnormality in these neonates seems to be an increase in pulmonary vascular resistance with an elevation of pulmonary artery pressure, right-left ductal shunting, preductal shunting and progressive hypoxemia. Eighteen neonates with a CDH were operated upon within the first 24 hours of life with a mortality of 38%. In no instance did ventilatory insufficiency seem to be a major factor in the death of the patient. Seven infants with progressive hypoxemia were treated with a vasodilator, tolazoline. Six of the seven infants showed an initial response to treatment, with a rise in preductal Pao2 and a decrease in ductal shunting. Four of these seven desperately ill neonates survived. Pathologic examination of the pulmonary vasculature in the nonsurvivors revealed an increase in muscle mass within the pulmonary arterioles. An exaggerated vasoconstrictive response of an abnormally hypertrophied pulmonary vascular bed leading to an elevation of pulmonary vascular resistance, rather than abnormalities of ventilation, appears to be the important mechanism leading to the often fatal hypoxemia observed in the neonate with a CDH. Improved survival will depend upon the successful management of the deranged pulmonary vascular hemodynamics seen in these infants.

From the Division of Pediatric Surgery, Department of Surgery, Stanford University Medical Center, Stanford, California and the Departments of Surgery, Pathology and Pediatrics, The Milton S. Hershey Medical Center, Pennsylvania State University, Hershey Pennsylvania

several recent series, still exceeds 50%.5,7,21 This high mortality, which is usually due to progressive hypoxemia, has historically been attributed to ventilatory insufficiency secondary to pulmonary hypoplasia. However, the primary abnormality in these neonates, as pointed out by Dibbins and Weiner4 and Collins et al.2, seems to be a persistence of a fetal type of circulation, with an increase in pulmonary vascular resistance, elevated pulmonary artery pressure and right-left ductal and preductal shunting leading to progressive hypoxemia. During the past four years, 18 infants under 24 hours of age were operated upon for repair of a CDH Hershey Medical Center and the Stanford University Medical Center. A high pulmonary vascular resistance with right-left ductal and preductal shunting was the major pathophysiological alteration observed in the neonates with progressive hypoxemia. Improved survival of these infants will depend upon the successful management of this pulmonary vascular at the Milton S.

T HE NEWBORN INFANT with a congenital diaphragmatic hernia (CDH) who develops severe respira-

tory distress requiring operative repair within the first 24 hours of life represents one of the most challenging problems in pediatric surgery. Despite improved surgical techniques, anesthetic management, postoperative respiratory care and intensive care facilities, the mortality in these infants has not changed appreciably over the past decade and, as reported in Presented at the Annual Meeting of the American Surgical Association, Hot Springs, Virginia, April 26-28, 1979. Reprint requests: Stephen J. Shochat, M.D., Chief, Division of Pediatric Surgery, Department of Surgery, Stanford University Medical Center, Stanford, California 94305.

hemodynamic abnormality. Clinical Data Eighteen neonates with a CDH were operated upon in the first 24 hours of life between April 1975 and March 1979 (Table 1). There were seven deaths, a mortality of 38%. The first baby in this series developed a contralateral pneumothorax while being transported. He required resuscitation in the neonatal intensive care unit and died immediately following surgical repair. The next three deaths occurred early in our series, prior to the use of vasodilators, and did not receive op-

0003-4932/79/0900/0332 $01.00 © J. B. Lippincott Company

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333

TABLE 1. Clinical Data and Blood Gas Analyses

Preoperative Case 1 2 3 4 5

6t 7t 8t 9 10 11 12 13

14t 15t 16t 17 18t

Age* (hr)

Birth Wt (g)

6 22 2 6 7 10 11 14 16 7 16 10 10 6 7 6 18 7

3850 3204 2700 2300 2750 3260 3544 3440 1956 3830 3180 3345 2700 2110 3000 3130 3000 4200

Apgar (1 min) 9 3 1 7 8 5 6 6 9 4 6 8 2 1 7 4

Site FiOZ

pH

Paco2 Pao2 AaDo2t (Torr) (Torr) (Torr)

Cap 0.32 7.45 UA UA UA TA UA UA UA UA UA UA UA UA RA TA UA RA

1.0 1.0 1.0 1.0 1.0 0.6 0.5 1.0 0.4 0.4 1.0 1.0 1.0 1.0 0.4 1.0

Postoperative

7.09 6.84 6.83 7.15 7.02 7.10 7.34 6.94 7.24 7.40 7.28 6.76 7.20 7.32 7.35 7.38

22.5 58.2 88.0 86.0 50.6 79.2 65.4 40.8 98.6 39.6 31.0 46.0 100.0 61.0 34.0 36.0 35.0

62 32 32 37 86 54 52 63 58 38 36 55 36 60 85 174 490

Site FiO2

PacO2 Pao2 AaD02 APao20 (Torr) (Torr) (Torr) (Torr)

pH

Cap 0.32 7.46 622 593 590 576 579 556

612 577 592 594 188

TA 1.0 7.26 TA 1.0 7.31 TA 1.0 7.40 TA 1.0 7.48 TA 1.0 7.38 RA 1.0 7.42 UA 0.4 7.36 TA 1.0 7.25 TA 0.56 7.45 RA 0.85 7.44 TA 0.53 7.40 TA 1.0 7.30 RA 1.0 7.36 RA 1.0 7.41 RA 0.40 7.37 RA 1.0 7.49

29 43 43 32 26 42 30 40 48 34 25 35 37 34 28 39 28

80 43 56 125 366 360 297 105 407 201 337 219 318 346 207 186 372

627 614 556 321 311 386

7 15 61 103 280 214

258

43

358 333 478

271 268 150

313

157

Outcome

Dead Alive Dead Dead Dead Alive Alive Alive Alive Alive Alive Alive Alive Dead Alive Dead Alive Dead

Cap = capillary; UA = umbilical artery; TA = temporal artery; RA = right radial artery; APao2 = difference between preductal and postductal Pao2 at an FiO2 of 1.0. * Birth to operation.

Fio2 of 1.0 (AaDo2

timum postoperative support. Seven infants were treated with a vasodilator, tolazoline, due to an increase in pulmonary vascular resistance with progressive hypoxemia. Four of these desperately ill neonates survived. The infants who died were younger and in more distress and were slightly smaller, as indicated by the mean values for age, birth weight and Apgar score (Table 2). However, there is considerable overlap within each group. Associated congenital cardiac anomalies or other associated anomalies were not seen in this group of infants. Caution must be used when comparing the mean pre-

operative and postoperative blood gas data (Table 2), since the management of these children varied greatly as a better understanding of the pathophysiology evolved. There is also great individual variability within each group. The postoperative blood gases recorded were those obtained shortly after operative repair or after the patient was stabilized in the immediate postoperative period. Except for Case 18, all patients who died and the four patients who survived following tolazoline therapy had preoperative PacO2 > 60 torr or AaDo2 > 500 torr. This blood gas picture is a bad prognostic indicator, as Raphaely and Downes had no survivors with a pre-

t Alveolar-arterial difference in partial pressure of oxygen at an = 760 - [Pao2 + Paco2 + 47]). t Infants who received tolazoline.

TABLE 2. Mean Values (Range) of Clinical Data and Blood Gas Analysis

Preoperative Age No.

Alive Without tolazoline With tolazoline Dead Without tolazoline With tolazoline

11 7

4 7 4 3

(hr)

Birth Weight (g)

14 3030 (7-22)* (1956-3830)

Apgar (1 min)

Paco2

AaDo,

(Torr)

(Torr)

44.9 (22.5-98.6) 64.0

Postoperative

Paco2

Pao2/Fi02

AaDo2

(Torr)

(Torr)

Pao2/Fi02

(Torr)

162 (55-435) 71

40 (25-48) 33

337

364 (250-465) 342

216

APao2

10

3311

6.7 (4-9) 5.5

(7-14)

(3000-3544)

(2-8)

582 [31t (50.6-79.2) (576-592) (54-86)

(26-42) (311-386) (297-366) (103-280)

5 (2-7) 6

2900 (2300-2850) 3146

2.0 [2] (1-3) 4.0

77.4 [3] 601 [3] (58.2-88.0) (590-622) 56.0 453

39 [3] 599 [3] (32-43) (556-627) 31 383

(6-7)

(2110-4200)

(1-8)

* Range. t Number of infants studied.

(34-100)

33 [3] (32-37) 203

75 [3] (43-125) 299

27 [3] (7-61) 192

(188-594) (36-490) (28-37) (313-478) (207-372) (150-271)

334

SHOCHAT AND OTHERS

operative AaDo2 greater than 500 torr21, and Dibbins and Weiner had only one survivor with an initial Paco2 greater than 60 torr.4 Elevated initial postoperative Paco2 was not seen in any of the patients who died, rul-

ing out ventilatory insufficiency with CO2 retention as a major factor in mortality. Excluding Case 1, only two patients who died failed to show an improvement in postoperative oxygenation (Cases 3 and 4). Postoperative AaDo2 revealed various degrees of preductal shunting. However, the mean postoperative AaDo2 of the three deaths in the tolazoline group compares favorably with the survival group, indicating that these infants were potentially salvageable. The Pao2/Fio2 ratio was

determined since many of the infants who survived without tolazoline did not receive an Fio2 of 1.0. The mean preoperative values are low in all groups. However, those patients who survived without tolazoline had a higher Pao2/Fio2 ratio than the other groups, if Case 18, in which the patient died with tolazoline, is excluded from this group (mean, 60). The postoperative mean Pao2/Fio2 ratios are comparable between the patients that survived and those who died following tolazoline therapy, again suggesting that these children are salvageable. The postoperative APao2 indicated a significant right-left ductal shunt in all patients receiving tolazoline and in one infant who died early in the series without tolazoline (Case 5). Two patients who survived without tolazoline (Case 10 and Case 13) had preoperative Paco, > 60 or AaDo, > 500; however, they did not have significant right-left ductal shunts postoperatively and did not develop progressive hypoxemia. The seven patients who received tolazoline followed similar clinical courses. All, except Case 18, had a predicted poor prognosis (Paco2 > 60 torr or AaDO2 > 500) and were monitored by measuring simultaneous preductal and postductal arterial blood gases. An initial improvement in the Pao2 was seen following surgery; however, a marked right-left ductal shunt was present or appeared in the immediate postoperative period. Clinical deterioration as manifested by progressive hypoxemia ensued, presumably due to increasing pulmonary arterial resistance. Six of the seven patients showed an initial response to tolazoline, with a rise in preductal Pao2 and a decrease in ductal shunting. The one patient who did not respond to tolazoline died. Three infants became refractory to this drug despite increasing concentrations, and two of these infants died. There were several complications associated with the use of tolazoline. Hypotension, tachycardia and a decreased urine output were seen in four infants. Minor episodes of gastrointestinal bleeding occurred in four patients. Two infants had unexplained seizures while receiving tolazoline. There were also two cardiac arrhythmias that may have been associated with tolazoline infusion, and one infant became thrombocytopenic.

Ann. Surg.

*

September 1979

All of the survivors are doing well without respiratory symptoms or neurologic deficits up to three years following operative repair. Many of the infants who received tolazoline had prolonged high preductal Pao2; however, there were no cases ofretrolental fibroplasia. The pulmonary vasculature of the patients in Cases 14 and 16 were studied pathologically and were found to contain an increased muscle mass when compared to age-matched controls.18 Details of the clinical course of three infants who received tolazoline are described. Case Reports Case 6. A 3260 g male infant of 36 weeks gestational age, was born with mild respiratory distress and cyanosis. A chest x-ray revealed a left diaphragmatic hernia. A nasogastric tube and endotracheal tube were inserted, and he was transferred to the Milton S. Hershey Medical Center. Blood gases with manual ventilation and an Fio2 of 1.0 showed pH, 7.15; Pac02, 50.6; Pao2, 86. A left diaphragmatic hernia was repaired at ten hours of age with creation of a ventral hernia and insertion of a left chest tube which was placed to 10-cm negative suction. A small hypoplastic left lung was seen at the time of surgery. Blood gases immediately after reduction revealed pH, 7.48; PacO, 26; Pao2, 366. Postoperatively he was placed on continuous positive airway pressure with an FiO2 of 1.0. Repeat blood gases showed a temporal artery pH of 7.28; Paco,2 23; Pao2, 212. (Umbilical artery pH, 7.33; Paco,2 36; Pao2, 109.) Blood pressure was 72/42. The Fi02 was decreased and his condition was stable four hours postoperatively with a pH of 7.39; Pac02, 32; Pao2, 118. A gradual deterioration in blood gases without response to increasing Fi02 followed, and tolazoline, 2 mg/kg/hour, was begun 24 hours postoperatively. Marked improvement in the temporal artery Pao2 occurred six hours following initiation of infusion, but a right-left ductal shunt was present. At 32 hours postoperatively, no ductal shunt was noted, and the Fio2 was decreased. Due to hypotension and a decreased urine output, tolazoline was gradually decreased and discontinued. He was extubated on postoperative day four. Chest xrays revealed gradual expansion of the left lung over the next seven days. Ventral hernia repair was performed on the 25th postoperative day. The remainder of his hospital course was uneventful. Eye examination was normal, without evidence of retrolental fibroplasia. He is now well, without pulmonary symptoms three years following surgery (Fig. 1). Case 14. A 2110 g female infant of 34 weeks gestational age, presented with respiratory distress at birth. An endotracheal tube was inserted, and a chest x-ray was taken which confirmed the diagnosis of a left diaphragmatic hernia. She was transferred to the Stanford University Medical Center, and initial blood gases following manual ventilation at an Fio2 of 1.0 revealed pH, 6.76; PacO2, 100; Pao2, 36. Tolazoline, 5 mg had been given intravenously prior to transfer. A left diaphragmatic hernia was repaired, and a small extralobar sequestration was resected. Due to a large diaphragmatic defect, a muscle flap was used for closure and a ventral hernia was constructed. A chest tube was placed in the left thoracic cavity and connected to 10 cm H20 negative suction. Postreduction intraoperative blood gases from a temporal artery catheter at an FiO2 of 1.0 revealed pH, 7.51; PacO2, 40; Pao2, 221. There was a marked right-left ductal shunt (umbilical artery Pao2, 76). She was placed on assisted ventilation with a peak inspiratory pressure of 40 cm H20, end expiratory pressure of 3 cm H20 and a rate of 60. Temporal artery blood gases on an FI02 of 1.0 showed a pH of 7.21; Pac%, 36; Pao2, 233. The right-left ductal shunt persisted with an umbilical artery Pao2 of 47. A right chest tube was inserted and con-

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3

FIG. 1. Clinical course and response of patient in Case 6 to tolazoline. Note episode of hypotension and tachycardia associated with tolazoline infusion.

HOURS nected to 10 cm negative suction. Preductal oxygenation improved during the immediate postoperative period, but a metabolic acidosis persisted and an episode of hypotension was treated with volume expansion. Blood gases at eight hours postoperatively from the temporal artery line revealed a pH of 7.30, Pac% of 37 and Pao2 of 318 at an Fio2 of 1.0. (Umbilical artery Pao2, 47). She gradually became more hypoxemic, and a tolazoline infusion, 2 mg/kg/hour, was begun 13 hours postoperatively. There was no response to tolazoline, despite an increase in the dosage to 4 mg/kg/hour. Progressive hypoxia, hypercarbia and acidosis ensued. She was given dopamine, glucagon and Dilanting without success and died 31 hours postoperatively. An autopsy was performed and was unremarkable, except for a hypoplastic left lung. The pulmonary vasculature was studied, and a significant increase in muscle mass was seen (Fig. 2). The mean muscle mass (area arterial media/area intimal nuclei) was 5.5 + 2.5 compared to that in an age-matched control of 3.91 + 2.79.18 Case 15. A 3000 g, term male infant developed severe respiratory distress shortly afterbirth, requiring endotracheal intubation. A chest

FIG. 2. Increased muscle

mass

x-ray revealed a left diaphragmatic hernia. He was transferred to the Stanford University Medical Center, where initial blood gases from a right radial artery catheter revealed a pH of 7.2, Pac,2 of 61 and Pao2 of 60 following mechanical ventilation at an Fio2 of 1.0. A left diaphragmatic hernia was repaired at seven hours of age. A small hypoplastic

left lung was seen, and a chest tube was placed with 8 cm H20 nega-

tive pressure. Mechanical ventilation was begun postoperatively with a peak inspiratory pressure of 30 cm H20, end expiratory pressure of 4, a rate of 40/min and an Fio2 of 1.0. A right chest tube was inserted. Radial artery blood gases revealed pH, 7.36, Pac02, 34; Pao2, 346; however, there was a marked right-left ductal shunt (umbilical artery Pao2, 78). The Fio2 was gradually decreased to 0.80 but had to be increased to 1.0 at eight hours postoperatively due to progressive hypoxia. (Radial artery pH, 7.45; Paco2, 28; Pao2, 86.) Hypoxemia persisted, and a tolazoline infusion, 2 mg/kg/hour, was begun, with a marked improvement in blood gases. (Radial artery pH, 7.44; PacO2, 32; Pao2, 329; umbilical artery Pao2, 269.) The tolazoline infusion was accidentally discontinued for one hour, resulting in a

within pulmonary arteriole of patient in Case 14 (B)

as

compared to

an

age-matched control (A).

SHOCHAT AND OTHERS

336

I

0

200

1111

180

4020 _

RIGHTRADIALARTERY* UMBILICAL ARTERY *

0

1

I I I I 3 5 7 9 11 13 15 17 19 21 23 25 27

Pre-op OP Post-op

1

37 39

HOURS

FIG. 3. Clinical course of Case 15. Note the influence of Fto2 variations, tolazoline, curare and an increased inspiratory pressure on oxygenation.

marked right-left ductal shunt (radial artery Pao2, 269; umbilical artery Pao2, 73). The infant again became severely hypoxic when the Fio was decreased to 0.90 but improved slightly following 1 mg of curare intravenously. Hypoxia was increased to 3 mg/kg/hour, gases. (Radial artery pH, 7.49;

recurred, and the tolazoline infusion with a striking improvement in blood Pac2, 28 Pao2, 303; umbilical artery pH, 7.49; Paco,2 30; PaO2, 250.) His condition again deteriorated but responded to an increase in the peak inspiratory pressure to 32 cm H20. Despite a significant and persistent right-left ductal shunt, he was able to tolerate decreasing Fio2 over the next 24 hours (Fig. 3). No significant right-left shunt was present by the fourth postoperative day. Tolazoline was gradually decreased and was discontinued on the seventh postoperative day. He was difficult to wean from the ventilator; however, he is now doing well at home with mild tachypnea 6 months postoperatively. Presently his chest x-ray reveals expansion of the left lung with mild overexpansion of the right.

Discussion Pathologic examination of the lungs of infants who have died with CDH reveals a decrease in size and weight, with the ipsilateral lung being the smaller and showing a distorted distribution of segmental airways. The airways are decreased in both lungs due to a reduction in the small bronchi and bronchioli. The reduction of total lung volume is due to a reduced total number of

Ann.

Surg. * September 1979

alveoli as a result of this deficiency in bronchiolar generation. These pathologic findings have lead to the assumption that the high mortality seen following repair of a diaphragmatic hernia is due to pulmonary hypoplasia. However, despite a reduction in total lung volume, the contralateral lung in infants with CDH usually is able to maintain ventilation. Our series of cases tends to support this observation, as initial postoperative CO2 retention suggesting ventilatory insufficiency was not seen in any of the fatalities. In surviving infants, the small hypoplastic ipsilateral lung eventually expands and fills the thoracic cavity. Hislop and Reid have shown that the lungs of infants who survive following repair of a CDH expand by increasing the size of the alveoli while maintaining a normal rate of multiplication.11 Total lung volume is normal, but there is an abnormal distribution, with the ipsilateral lung contributing only 40%. Pulmonary function studies performed on children who have had CDH repaired as infants confirm the above observations in that total lung capacity and vital capacity are normal.25 However, a consistent abnormality seen in all patients studied by xenon radiospirometry was a reduced blood flow to the lung on the side of the hernia. The strongest argument against the theory that pulmonary hypoplasia and ventilatory insufficiency contribute to the mortality in CDH is the common clinical pattern that is usually seen in those neonates dying following repair of a diaphragmatic hernia. There is a marked improvement in oxygenation in the immediate postoperative period, followed by deterioration 12-24 hours postoperatively, with progressive hypoxemia, acidosis, hypercarbia and death, despite all therapeutic manipulations. Four of our seven deaths followed this clinical course. Murdock et al.'7 and Rowe and Uribe22 were the first to measure simultaneous preductal (temporal or radial artery) and postductal (umbilical artery) Pao2s in infants with CDH. They showed that there were large alveolar-arterial oxygen tension differences between the radial or temporal artery and descending aorta in the presence of adequate alveolar ventilation as measured by normal PacO2. They suggested that in addition to intrapulmonary shunting and shunting across the foramen ovale there must be relatively large volumes of venous admixture through the ductus arteriosus. Subsequent clinical studies of neonates with CDH were carried out by Dibbins and Weiner4 and Collins et al.,2 and the major role of the pulmonary circulation in determining the outcome of these infants was stressed. Using paired arterial samples drawn above and below the ductus, evidence of preductal and ductal right-left shunting was demonstrated. Postoperative improvement was associated with a decrease in both preductal

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CONGENITAL DIAPHRAGMATIC HERNIA

and ductal shunting, while episodes of clinical deterioration could be identified as severe progressive hypoxemia accompanied by preductal shunting. Cardiac catheterization studies have been performed in children with CDH and demonstrate pulmonary arterial hypertension with a right-left shunt across the ductus, elevated right ventricular end diastolic pressure and elevated right atrial pressure with shunting across the foramen ovale. Pulmonary angiography shows a decreased total pulmonary flow with shunting across the ductus and almost no perfusion of the lung on the side of the diaphragmatic hernia. The pulmonary vasculature of infants who have died with CDH has been investigated. Naeye et al found a significant increase in muscle mass in the small pulmonary arteries in ten of 12 children with CDH when compared to age-matched controls.18 In each infant with a diaphragmatic hernia, the muscle values were almost identical in the two lungs. Levin has confirmed this finding and also found that there was a decrease in the total size of the pulmonary vascular bed, as well as a decrease in the number ofvessels per unit oflung. 12 The abnormally large mass of muscle within the small pulmonary arteries in infants with CDH is present at birth and is probably associated with various degrees of intrauterine fetal distress or hypoxia. This muscular hypertrophy could also develop as a result of mechanical distortion of the fetal ductus arteriosus due to the mediastinal shift caused by the diaphragmatic hernia. Partial constriction of the ductus would increase the pulmonary blood flow through a smaller than normal vascular bed, resulting in pulmonary hypertension, which has been shown to cause excessive pulmonary arterial smooth muscle in fetal lambs. 12 The degree of muscle hypertrophy may depend upon the timing of the intrauterine events leading to the development of the diaphragmatic hernia and could explain the variable clinical course seen in infants following operative reduction. The observation that there is an inverse relationship between pulmonary arterial muscle mass and relative lung weights would tend to support this theory.'8 This anatomically abnormal pulmonary vascular bed in infants with CDH is capable of an exaggerated response to factors which produce pulmonary vasoconstriction in the newborn period. There are numerous factors that affect pulmonary vascular tone (Fig. 4). The interaction of these various factors probably plays a major role in initiating the increase in pulmonary vascular resistance which results in the progressive hypoxemia and high mortality following repair of a CDH. Alveolar hypoxia is one of the most potent stimuli leading to pulmonary vasoconstriction, and a large

337

VENTILATORY AND METABOLIC FACTORS 1) VENTILATION WITH OXYGEN

2) HYPERVENTILATION

1) ALVEOLAR HYPOXIA 2) HYPOXEMIA 5)HYPOTHERMIA 3) HYPERCARBIA 6) ? INCREASES IN TRANSPULMONARY PRESSURE 4) ACIDOSIS

~'

ACETYLCHOLINE HISTAMINE BRADYKININ GLUCAGON PROSTAGLANDIN 6) TOLAZOLINE

1) 2) 3) 4) 5)

,/

=

A~~~~~~

1) EPINEPHRINE

7) ISOPRENALINE 8) CHLORPROMAZINE 9) NITROPRUSSIDE 10) DILANTIN

2) NOREPINEPHRINE 3) SEROTONIN 4) PROPRANOLOL

E

1-\ z;/,

11) CURARE 12) HALOTHANE

ENDOGENOUS SUBSTANCES AND DRUGS

FIG. 4. Factors that affect pulmonary vascular tone. A) Vasodilatation, decreased pulmonary arterial resistance, increased pulmonary blood flow; B) vasoconstriction, increased pulmonary arterial resistance, decreased pulmonary blood flow.

muscle mass in the pulmonary arterioles seems to enhance this pressor response.6 Alveolar hypoxia is certainly present preoperatively in the neonate with CDH and probably persists in the ipsilateral lung postoperatively, despite expansion of the contralateral lung. The hypoplastic lungs of the fetal lamb have been found to have a reduced compliance, and inflation pressures of 35 cm H20 or more are required to open alveoli.23 Alveolar hypoxia could also explain why seemingly small reductions in the FiO2 of infants following repair of a CDH are frequently followed by an increase in rightleft shunting, presumably due to pulmonary vasospasm, despite the presence of a normal Pao2. This observation has frequently been seen in our patients postoperatively (Fig. 3). The etiology of pulmonary arteriolar vasoconstriction secondary to alveolar hypoxia is not known, but vasoactive substances or a reflex mechanism may be involved. Alveolar hypoxia may also have a direct vasospastic effect on the arterioles. Hypoxemia can cause pulmonary vasospasm, and this effect can be seen independent of alveolar hypoxia.6 Acidosis, hypercarbia and hypothermia are also associated with pulmonary vasoconstriction and increased pulmonary vascular resistance. The relative effects of hypoxemia and acidosis in producing pulmonary arteriolar vasoconstriction are not clear but are most likely synergistic. An increase in transpulmonary pressure has recently been shown to be associated with hypoxemia and respiratory insufficiency in newborn puppies.20 While pulmonary artery pressures were not measured, it was inferred that increased trans-

338

SHOCHAT AND OTHERS

pulmonary pressure could initiate pulmonary arteriolar vasoconstriction leading to progressive hypoxemia. The exact role played by pulmonary vascular volume, pulmonary blood flow and the ductus arteriosus in children with CDH is not clearly understood. The infant with a CDH and a normal blood volume must force most of the right ventricular output through the contralateral pulmonary vascular bed until the ipsilateral lung expands. This leads to an overdistended unilateral pulmonary circulation with elevated pulmonary arterial, right ventricular end diastolic and right atrial pressures. In addition, there is a diminished cross-sectional area of the vascular bed due to an increase in musculature, compounded by pulmonary vasoconstriction. The end result is severe desaturation of the systemic circulation due to massive right-left shunting across the ductus and foramen ovale. Dibbins and Weiner feel that the ductus serves as a vent, preventing right ventricular failure until relaxation of the pulmonary vascular bed occurs with expansion of the ipsilateral lung.4 The ductus, however, can shunt enough desaturated blood into the systemic circulation to produce hypoxemic tissue acidosis, which will increase pulmonary vasoconstriction. This fact has lead to the suggestion by Collins et al. that the ductus arteriosus should be ligated in infants with progressive hypoxemia following repair of CDH.2 They believe this will increase pulmonary blood flow and pulmonary artery pressure with an improvement in peripheral oxygenation, the patent foramen ovale protecting against right heart failure. There is some evidence that increased pulmonary blood flow can relieve the vasoconstriction associated with hypoxial; however, the clinical results of ductus ligation without pharmacologic lowering of the pulmonary vascular resistance have not been en2

couraging.

Regardless of the roles played by pulmonary blood flow and the ductus arteriosus, the main concern in these infants is the relief of pulmonary vasoconstriction and a decrease in pulmonary vascular resistance. High negative intrathoracic pressures on the ipsilateral side should be avoided due to the possible vasoconstrictive effects of increased transpulmonary pressure. Improving ventilatory mechanics by hyperventilation and providing high inspiratory oxygen concentrations will help relieve alveolar hypoxia, hypoxemia, acidosis and hypercarbia. A contralateral chest tube should be inserted prophylactically. Peckham and Fox have shown the validity of hyperventilation in infants with the clinical syndrome of persistent fetal circulation, a condition pathophysiologically similar to that of the infant with a CDH, by monitoring pulmonary artery pressure during treatment. '9 The pulmonary arterial pressures fell in all patients with a decrease in pulmonary vascular

Ann. Surg. * September 1979

resistance, a decrease in AaD02 and improved oxygenation. Mechanical ventilation with high inflating pressures and high rates were maintained to control the Paco2 in the 25-30 mmHg range. If a large right-left ductal shunt or preductal shunt persists after satisfactory ventilation is established, as determined by a normal Paco2 and pH, then pharmacologic measures to lower pulmonary vascular resistance will be required. There were no survivors in the present series with large postoperative preductal or ductal shunts who did not receive pharmacologic support with tolazoline. Many endogenous substances and drugs affect pulmonary vascular tone,'4 as depicted in Figure 4. Acetylcholine has been used with some success in children with CDH but must be infused through a pulmonary artery catheter, as it is neutralized rapidly in the blood stream. Chlorpromazine has been tried by Dibbins with a satisfactory response in one surviving infant.3 Curare seems to be beneficial by increasing effective ventilation due to increased chest wall compliance as well as by releasing histamine, which is a pulmonary vasodilator in man'3 (Fig. 3). Halothane has been shown to inhibit the vasoconstrictive response of alveolar hypoxia but has not been studied clinically. Dilantin, nitroprusside and glucagon have also been used experimentally to dilate the pulmonary vascular bed. However, tolazoline is the drug that has been used most extensively in the treatment of the clinical syndrome of persistent fetal circulation8"13'24 and has recently been used successfully in neonates with CDH.15"16 Tolazoline is primarily an alpha adrenergic blocking agent; however, it also has a direct nonadrenergic relaxant effect on vascular smooth muscle. Tolazoline also has a direct inotropic effect on the heart, which is mediated through histamine receptors. It is chemically related to the sympathomimetic amines and histamine. Seven neonates were treated with tolazoline because of progressive hypoxemia following repair of a CDH. Six infants showed an initial response to an infusion of 2 mg/kg/hour (Figs. 1 and 3), and four infants survived. Three infants showed an initial response but became refractory to increasing concentrations, up to 8 mg/kg/ hour. Two of these infants died due to progressive hypoxemia and acidosis, and one infant survived after a prolonged period of hypoxemia. These cases of tachyphylaxis associated with the use of tolazoline are not uncommon. The infant who showed no response to tolazoline received a bolus infusion prior to operative repair, which may have been related to her failure to respond postoperatively; however, this infant also had a persistent metabolic acidosis. Autopsy in this child revealed a significant increase in pulmonary arteriolar muscle mass (Fig. 2). Several complications were associated with the use

Vol. 190 * No. 3

CONGENITAL DIAPHRAGMATIC HERNIA

of tolazoline, which is consistent with the experience of others who have noted a high complication rate.24 Hypotension, tachycardia and decreased urine output were frequent complications. Hypotension can usually be treated with blood volume expansion; however, pharmacologic support may be required. Gastrointestinal bleeding was seen and is thought to be due to increased gastric secretion secondary to the histamine-like action of tolazoline. The episodes of gastrointestinal bleeding were mild and were controlled by conservative means. Thrombocytopenia, seizure activity and cardiac arrhythmias were also seen and may have been related to tolazoline therapy. None of the above complications contributed directly to the mortality seen in these infants. While tolazoline may effectively lower the pulmonary vascular resistance in neonates with CDH, careful and continuous monitoring of these infants is required as potentially fatal complications are associated with its use. An agent that may have potential usefulness in children following repair of CDH is prostaglandin E1 (PGE1). Experimentally, PGE1 inhibits the pulmonary vascular pressor response to hypoxia and can reduce the pulmonary hypertension caused by prostaglandin F2. Prostaglandin E1 has been used clinically to manage the critically ill neonate with ductus dependent cyanotic congenital heart disease with few complications. Pyrexia, peripheral vasodilation, tremors and mild focal seizures have been reported.9 One patient who showed a striking improvement in oxygenation after receiving PGE1 was later found to have a closed ductus. The improved oxygenation was thought to be due to a reduction in the pulmonary vascular resistance by

PGEI.9 Several animal models have been developed in order to study the hemodynamic and ventilatory changes that are associated with CDH.10'23 Increased pulmonary artery pressures, decreased perfusion of the ipsilateral lung at birth, varying degrees of right-left shunting and decreased lung compliance have been demonstrated. However, these studies have been disappointing to date due to their inability to consistently reproduce the clinical situation which is usually encountered following repair of a CDH. The rapid pathophysiological changes that occur postoperatively in these infants require constant observation and continuous monitoring of various parameters. Until recently, it was not possible to continuously monitor the rapid changes that were occurring in Pao2 following repair of a CDH. However, the development of the transcutaneous oxygen electrode will enable continuous monitoring of preductal and postductal Pao2 in the critically ill infants, so that therapeutic decisions can be made early prior to signifi-

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cant clinical deterioration. Another recent advance that will aid in the management of neonates with CDH is the development of a small, flow-directed, balloontipped catheter which can be placed in the pulmonary artery without requiring cardiac catheterization. Continuous monitoring of pulmonary artery pressure should be helpful in determining the efficacy of various therapeutic modalities. The clinical data presented in this report and the abundant pathologic and physiologic data that have been gathered in recent years clearly emphasize the important role played by the pulmonary vasculature in the survival of neonates with CDH. An exaggerated vasoconstrictive response of an abnormally hypertrophied pulmonary vascular bed leading to an elevation of the pulmonary vascular resistance appears to be the important mechanism leading to the often fatal hypoxemia seen in these neonates. A better understanding ofthe initiating factors leading to this deranged pathophysiology is imperative and, hopefully, will be aided by the design of more appropriate animal models. The investigation and development of more effective and safer pharmacologic agents capable of reversing pulmonary arteriolar vasoconstriction will facilitate the successful management and improve the survival of these critically ill infants.

Acknowledgment We wish to thank Kathleen Gifford, R.N., and Karen McKinley, R.N., for their help in collecting the clinical data and Ms. Linda Watkins for her excellent secretarial assistance. We would also like to thank Dr. A. W. Dibbins for his helpful suggestions concerning the pathophysiology of these neonates and all the nursing and resident staff who devoted so much of their time to the care of these infants.

References 1. Benumoe, J. L. and Wahrenbrock, E. A.: Blunted Hypoxic Pul-

2. 3. 4. 5. 6.

7. 8. 9.

monary Vasoconstriction by Increased Lung Vascular Pressures. J. Appl. Physiol., 38:846, 1975. Collins, D. L., Pomerance, J. J., Travis, K. W. et al.: A New Approach to Congenital Posterolateral Diaphragmatic Hernia. J. Pediatr. Surg., 12:149, 1977. Dibbins, A. W.: Neonatal Diaphragmatic Hernia: A Physiologic Challenge. Am. J. Surg., 131:408, 1976. Dibbins, A. W. and Weiner, E. S.: Mortality From Neonatal Diaphragmatic Hernia. J. Pediatr. Surg., 9:653, 1974. Ehrlich, F. E. and Salzberg, A. M.: Pathophysiology and Management of Congenital Posterolateral Diaphragmatic Hernias. Am. Surg., 44:26, 1978. Fishman, A. P.: Hypoxia on the Pulmonary Circulation: How and Where It Acts. Circ. Res., 38:221, 1976. Fitzgerald, R. J.: Congenital Diaphragmatic Hernia: A Study of Mortality Factors. Ir. J. Med. Sci., 146:280, 1977. Goetzman, B. W., Sunshine, P., Johnson, J. D. et al.: Neonatal Hypoxia and Pulmonary Vasospasm: Response to Tolazoline. J. Pediatr., 89:617, 1976. Graham, T. P., Jr., Atwood, G. F. and Boucek, R. J., Jr.: Pharmacologic Dilatation of the Ductus Arteriosus With Prostaglandin E, in Infants with Congenital Heart Disease. South. Med. J., 71:1238, 1978.

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10. Haller, J. A., Jr., Signer, R. D., Golladay, E. S. et al.: Pulmonary and Ductal Hemodynamics in Studies of Simulated Diaphragmatic Hernia of Fetal and Newborn Lambs. J. Pediatr. Surg., 5:675, 1976. 11. Hislop, A. and Reid, L.: Persistent Hypoplasia of the Lung After Repair of Congenital Diaphragmatic Hernia. Thorax, 31:450, 1976. 12. Levin, D. L.: Morphologic Analysis of the Pulmonary Vascular Bed in Congenital Left-Sided Diaphragmatic Hernia. J. Pediatr., 92:805, 1978. 13. Levin, D. L., Heymann, M. A., Kitterman, J. A. et al.: Persistent Pulmonary Hypertension of the Newborn Infant. J. Pediatr., 89:626, 1976. 14. Levin, D. L., Cates, L., Newfeld, E. A. et al.: Persistence of the Fetal Cardiopulmonary Circulatory Pathway: Survival of an Infant After a Prolonged Course. Pediatrics, 56:58, 1975. 15. Levy, R. J., Rosenthal, A., Freed, M. D. et al.: Persistent Pulmonary Hypertension in a Newborn with Congenital Diaphragmatic Hernia: Successful Management With Tolazoline. Pediatrics, 60:740, 1977. 16. Moodie, D. S., Telander, R. L., Kleinberg, F. and Feldt, R. H.: Use of Tolazoline in Newborn Infants With Diaphragmatic Hernia and Severe Cardiopulmonary Disease. J. Thorac. Cardiovasc. Surg., 75:725, 1978. 17. Murdock, A. I., Burrington, J. B. and Swyer, P. R.: Alveolar to Arterial Oxygen Tension Difference and Venous Admixture in Newly Born Infants with Congenital Diaphragmatic Hernia-

DISCUSSION

DR. LESTER WARREN MARTIN (Cincinnati, Ohio): We also have used tolazoline, or Priscoline, in some of our infants with diaphragmatic hernia. Our problem is evaluating our results to determine whether the baby would have become well without it. To try to determine this, we have placed our infants in three simple categories. One is a group with normal blood gases. We feel those babies should get well without Priscoline. The second group consists of those infants with abnormal blood gases that can be corrected by mechanical ventilation. We feel those infants are also potentially salvageable without the aid of other agents. The third group is the infants with abnormal preoperative blood gases that cannot be corrected with mechanical ventilation. These are the infants who, in our experience, have all died. There is evidence to indicate that their problem is persistent fetal circulation. The pulmonary vascular resistance forces the blood to continue going through the ductus, bypassing the lungs. Theoretically, the Priscoline should produce pulmonary vasodilation and permit the flow of blood through the pulmonary vascular bed. Priscoline, however, also causes peripheral vasodilation with a resultant undesirable fall of systemic pressure. Some have advocated administration of Priscoline directly into the pulmonary artery by way of a small Swan-Ganz type catheter. Ligation of the ductus has also been suggested, but temporary occlusion of the ductus in two of our infants resulted in significant bradycardia and systemic hypotension. I wish to ask Dr. Shochat if any of the Priscoline-treated survivors had preoperative acidosis which could not be corrected by mechanical ventilation. If so, then Priscoline would appear to be of significant value. DR. J. ALEX HALLER, JR. (Baltimore, Maryland): Three years ago we had a workshop in the Surgical Section of the Academy of Pediatrics on diaphragmatic hernia in an attempt to collate our clinical experience throughout the country, and I thought it might be helpful to review quite briefly with you some of those points of discussion, because I realize that many of you are not constantly dealing with this problem. (slide) One of the most important aspects of Dr. Shochat's presentation is the focus on why we are losing 50% of the babies born with a hole in the diaphragm, because we certainly have the operative

18. 19.

20. 21.

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Ann. Surg. * September 1979

tion Through the Foramen of Bochdalek. Biol. Neonate, 17:161, 1971. Naeye, R. L., Shochat, S. J., Whitman, V. and Maisels, M. J.: Unsuspected Pulmonary Vascular Abnormalities Associated With Diaphragmatic Hernia. Pediatrics, 58:902, 1976. Peckham, G. J. and Fox, W. W.: Physiologic Factors Affecting Pulmonary Artery Pressure in Infants With Persistent Pulmonary Hypertension. J. Pediatr., 93:1005, 1978. Ramenofsky, M. L.: The Effects of Intrapleural Pressure on Respiratory Insufficiency. Presented at the 10th Annual Meeting of the American Pediatric Surgical Association, 1979. Raphaely, R. C. and Downes, J. J., Jr.: Congenital Diaphragmatic Hernia: Prediction of Survival. J. Pediatr. Surg., 8:815, 1973. Rowe, M. 1. and Uribe, F. L.: Diaphragmatic Hernia in the Newborn Infant: Blood Gas and pH Considerations. Surgery, 70:758, 1971. Starrett, R. W. and deLorimier, A. A.: Congenital Diaphragmatic Hernia in Lambs: Hemodynamic and Ventilatory Changes with Breathing. J. Pediatr. Surg., 10:575, 1975. Stevenson, D. K., Kasting, D. S., Darnall, R. A. et al.: Refractory Hypoxemia Associated With Neonatal Pulmonary Disease: The Use and Limitations of Tolazoline. J. Pediatr., submitted for publication. Wohl, M. E. B., Griscom, N. T., Strieder. D. J. et al.: The Lung Following Repair of a Congenital Diaphragmatic Hernia. J. Pediatr., 90:405, 1977.

techniques to correct it. In perspective. a baby who lives longer than 48 hours with a diaphragmatic defect will survive in almost 100% of the situations. Babies less than 24 hours old who have severe respiratory distress have a frustratingly high mortality rate (50%). In our workshop many of the principles which Dr. Shochat outlined were discussed, and some of the recommendations which he presented were also outlined. I believe that he is the first to report the use of some of those techniques. (slide) When we evaluated the clinical results around the country, several important points were obvious. First, as Dr. Shochat has pointed out, we were not losing these babies because they had inadequate pulmonary function or inadequate tissue. There were a few who died of lethal abnormalities. One of the striking features of this particular congenital abnormality is that it is usually isolated. Therefore, if we could help these children, we would be dealing with an otherwise perfectly normal child with an excellent life expectancy. The second point was that intrathoracic tension and compression were responsible for underdevelopment of the lung. A few children had insufficient lung tissue, but they could always be detected, because it was impossible, in spite of good ventilation, to lower their Pak02's. Thus, as Dr. Martin has indicated, we are able to identify a group of patients who demonstrate progressive hypoxemia and acidosis. The real question is: What is wrong with them, and why do we have this continuing loss? (slide) A few may fit into this category of mechanical problems in the lung, with rupture, hyperinflation, etc.: but it seems to be primanily this problem of persistent fetal circulation, with right-to-left shunting at both the level of the patent foramen ovale and the patent ductus. (slide) For those of you who have not thought about fetal circulation for a while, you may recall that as the blood returns in the fetus to the right atrium, it is shunted both through the foramen ovale and also through the ductus arteriosus. The neonatologists are now calling this condition, in which there is a failure of relaxation of the pulmonary vascular bed, persistent fetal circulation. This appears to be the primary problem. (slide) There are ways of approaching this experimentally, and a number of us have been working at creating a congenital diaphragmatic hernia model. (slide) When you do this, it is possible to show hypoplasia of the lung. You can even ligate the left pulmonary artery, but in none